regorafenib (Rx)

Brand and Other Names:Stivarga
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 40mg
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Colorectal Cancer

Indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild type, an anti-EGFR therapy

160 mg (four 40-mg tablets) PO qDay for the first 21 days of each 28-day cycle

Continue treatment until disease progression or unacceptable toxicity

Also see Administration

Gastrointestinal Stromal Tumors

Indicated for the treatment of locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) in patients who have been previously treated with imatinib mesylate and sunitinib

160 mg (four 40-mg tablets) PO qDay for the first 21 days of each 28-day cycle

Continue treatment until disease progression or unacceptable toxicity

Also see Administration

Hepatocellular Carcinoma

Indicated for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

160 mg (four 40-mg tablets) PO qDay for the first 21 days of each 28-day cycle

Continue treatment until disease progression or unacceptable toxicity

Also see Administration

Dosage Modifications

Interrupt dose

  • Grade 2 hand-foot skin reaction (HFSR)/palmar-plantar erythrodysesthesia (PPES) that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR
  • Symptomatic Grade 2 hypertension
  • Any Grade 3 or 4 adverse reaction

Reduce dose to 120 mg/day

  • For the first occurrence of Grade 2 HFSR of any duration
  • After recovery of any Grade 3 or 4 adverse reaction except infection
  • For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation; only resume if the potential benefit outweighs the risk of hepatotoxicity

Reduce dose to 80 mg/day

  • For reoccurrence of Grade 2 HFSR at the 120 mg dose
  • After recovery of any Grade 3 or 4 adverse reactions at the 120 mg dose (except hepatotoxicity or infection)

Discontinue permanently

  • Failure to tolerate 80 mg dose
  • Any occurrence of AST/ALT >20x ULN
  • Any occurrence of AST/ALT >3x ULN with concurrent bilirubin >2x ULN
  • Reoccurrence of AST/ALT >5x ULN despite dose reduction to 120 mg
  • For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks

Renal Impairment

  • Mild-to-severe: No dosage adjustment necessary
  • Patients on dialysis: Not studied

Hepatic Impairment

  • Mild (total bilirubin ≤ULN and AST>ULN, or total bilirubin >ULN to ≤1.5x ULN) or moderate (total bilirubin >1.5 to ≤3x ULN and any AST): No dosage adjustment necessary
  • Severe (total bilirubin >3x ULN): Not recommended; not studied

Safety and efficacy not established

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Interactions

Interaction Checker

and regorafenib

No Results

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            All grades of severity are listed unless otherwise indicated

            >10% (Colorectal Cancer)

            Anemia (79%)

            Increased AST (65%)

            Asthenia (64%)

            Proteinuria (60%)

            Hypocalcemia (59%)

            Hypophosphatemia (57%)

            Lymphopenia (54%)

            Decreased appetite and food intake (47%)

            Increased lipase (46%)

            HFSR/PPES (45%)

            Hyperbilirubinemia (45%)

            Increased ALT (45%)

            Diarrhea (43%)

            Thrombocytopenia (41%)

            Mucositis (33%)

            Weight loss (32%)

            Infection (31%)

            Hypophosphatemia, Grade 3 or 4 (31%)

            Hypertension (30%)

            Dysphonia (30%)

            Hyponatremia (30%)

            Pain (29%)

            Fever (28%)

            Rash (26%)

            Hypokalemia (26%)

            Increased amylase (26%)

            Increased INR (24%)

            Hemorrhage (21%)

            Nausea (20%)

            HFSR/PPES, Grade 3 or 4 (17%)

            Asthenia/fatigue, Grade 3 or 4 (15%)

            >10% (GIST)

            HFSR/PPES (67%)

            Pain (60%)

            Hypertension (59%)

            Proteinuria (59%)

            Increased AST (58%)

            Hypophosphatemia (55%)

            Asthenia (52%)

            Diarrhea (47%)

            Mucositis (40%)

            Dysphonia (39%)

            Increased ALT (39%)

            Hyperbilirubinemia (33%)

            Infection (32%)

            Decreased appetite and food intake (31%)

            Rash (30%)

            Lymphopenia (30%)

            Alopecia (24%)

            ever (21%)

            HFSR/PPES, Grade 3 or 4 (22%)

            Hypokalemia (21%)

            Nausea (20%)

            Hypophosphatemia, Grade 3 or 4 (20%)

            Hypothyroidism (18%)

            Vomiting (17%)

            Hypocalcemia (17%)

            Headache (16%)

            Neutropenia (16%)

            Weight loss (14%)

            Increased lipase (14%)

            Muscle spasms (14%)

            Thrombocytopenia (13%)

            Hemorrhage (11%)

            >10% (HCC)

            Increased AST (93%)

            Hyperbilirubinemia (78%)

            Hypophosphatemia (70%)

            Increased ALT (70%)

            Lymphopenia (68%)

            Thrombocytopenia (63%)

            Pain (55%)

            Proteinuria (51%)

            HFSR/PPES (51%)

            Increased INR (44%)

            Asthenia/fatigue (42%)

            Diarrhea (41%)

            Increased lipase (41%)

            Hypophosphatemia, Grade 3 or 4 (31%)

            Hypertension (31%)

            Infection (31%)

            Hypokalemia (31%)

            Decreased appetite and food intake (31%)

            Hypocalcemia (23%)

            Increased amylase (23%)

            Fever (20%)

            Hypothyroidism (18%)

            Hemorrhage (18%)

            Dysphonia (18%)

            Nausea (17%)

            Hypocalcemia (17%)

            Proteinuria, Grade 3 or 4 (17%)

            Headache (16%)

            Hypertension, Grade 3 or 4 (15%)

            Neutropenia (14%)

            Mucositis (13%)

            Vomiting (13%)

            Weight loss (13%)

            Hyperbilirubinemia, Grade 3 or 4 (13%)

            HFSR/PPES, Grade 3 or 4 (12%)

            Increased lipase, Grade 3 or 4 (11%)

            1-10% (Colorectal Cancer)

            Headache (10%)

            Hyperbilirubinemia, Grade 3 or 4 (10%)

            Pain, Grade 3 or 4 (9%)

            Infection, Grade 3 or 4 (9%)

            Increased lipase, Grade 3 or 4 (9%)

            Lymphopenia, Grade 3 or 4 (9%)

            Hypertension, Grade 3 or 4 (8%)

            Diarrhea, Grade 3 or 4 (8%)

            Hypokalemia, Grade 3 or 4 (7%)

            Musculoskeletal stiffness (6%)

            Rash, Grade 3 or 4 (6%)

            Decreased appetite and food intake, Grade 3 or 4 (5%)

            Anemia, Grade 3 or 4 (5%)

            Increased AST/ALT, Grade 3 or 4 (6%)

            Mucositis, Grade 3 or 4 (4%)

            Hypokalemia, Grade 3 or 4 (4%)

            Neutropenia (3%)

            Tremor (2%)

            Hemorrhage, Grade 3 or 4 (2%)

            Fever, Grade 3 or 4 (2%)

            Proteinuria, Grade 3 or 4 (2%)

            Increased amylase, Grade 3 or 4 (2%)

            Neutropenia, Grade 3 or 4 (1%)

            Hypocalcemia, Grade 3 or 4 (1%)

            1-10% (GIST)

            Lymphopenia, Grade 3 or 4 (8%)

            Pain, Grade 3 or 4 (8%)

            Diarrhea, Grade 3 or 4 (8%)

            Rash, Grade 3 or 4 (8%)

            Infection, Grade 3 or 4 (5%)

            Asthenia/fatigue, Grade 3 or 4 (4%)

            Hemorrhage, Grade 3 or 4 (4%)

            Increased AST/ALT, Grade 3 or 4 (3-4%)

            Hyperbilirubinemia, Grade 3 or 4 (3%)

            Proteinuria, Grade 3 or 4 (3%)

            Hypokalemia, Grade 3 or 4 (3%)

            Neutropenia, Grade 3 or 4 (2%)

            Mucositis, Grade 3 or 4 (2%)

            Nausea, Grade 3 or 4 (2%)

            Hypocalcemia, Grade 3 or 4 (2%)

            Thrombocytopenia, Grade 3 or 4 (1%)

            1-10% (HCC)

            Muscle spasms (10%)

            Asthenia/fatigue, Grade 3 or 4 (10%)

            Infection, Grade 3 or 4 (8%)

            Increased ALT, Grade 3 or 4 (6%)

            Hemorrhage, Grade 3 or 4 (5%)

            Thrombocytopenia, Grade 3 or 4 (5%)

            Neutropenia, Grade 3 or 4 (4%)

            Diarrhea, Grade 3 or 4 (3%)

            Diarrhea, Grade 3 or 4 (3%)

            Decreased appetite or food intake (3%)

            Weight loss (2%)

            Mucositis, Grade 3 or 4 (1%)

            <1%

            GIST

            • Decreased appetite and food intake, Grade 3 or 4
            • Vomiting, Grade 3 or 4

            HCC

            • Nausea
            • Vomiting
            • Increased INR

            Colorectal cancer

            • Headache, Grade 3 or 4

            Postmarketing Reports

            Hypersensitivity reactions

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            Warnings

            Black Box Warnings

            Hepatotoxicity

            • Severe and sometimes fatal hepatotoxicity observed in clinical trials
            • Monitor hepatic function prior to and during treatment
            • Interrupt and then reduce or discontinue for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence
            • Also see Dosage Modifications and Cautions

            Contraindications

            None

            Cautions

            Also see Dosage Modifications

            May cause severe drug-induced liver injury with fatal outcome (see Black Box Warnings); obtain liver function tests (ALT, AST, and bilirubin) before initiation of therapy and monitor at least every 2 weeks during first 2 months of treatment; thereafter, monitor monthly or more frequently as clinically indicated; monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline; temporarily hold and then reduce or permanently discontinue therapy depending on severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis

            Increases risk for hemorrhage; discontinue therapy for severe or life-threatening hemorrhage

            Increased risk of infections reported; most common infections include urinary tract infections, nasopharyngitis, mucocutaneous and systemic fungal infections and pneumonia

            Increases risk for HFSR/PPES and rash; a higher incidence of HFSR reported in Asian patients; interrupt and then reduce or discontinue regorafenib depending on severity and persistence of dermatologic toxicity

            Hypertension may occur, typically during the first treatment cycle; do not initiate therapy unless blood pressure is adequately controlled; monitor blood pressure weekly for first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated; temporarily or permanently withhold therapy for severe or uncontrolled hypertension

            Myocardial ischemia and infarction observed in clinical trials; withhold regorafenib for new or acute cardiac ischemia/infarction and resume only after resolution of acute ischemic events

            One case report of reversible posterior leukoencephalopathy syndrome (RPLS) reported (1 of 1100 treated patients); discontinue therapy if RPLS occurs

            Discontinue therapy if gastrointestinal perforation or fistula occur

            May impair wound healing (class effect of VEGFR inhibitors); discontinue at least 2 weeks before scheduled surgery; discontinue therapy in patients with wound dehiscence

            Embryo-fetal toxicity likely if taken while pregnant (see Pregnancy & Lactation)

            Drug interactions overview

            • Strong CYP3A4 inhibitors
              • Coadministration with strong CYP3A4 inhibitors increases regorafenib plasma concentrations, decreased active metabolite (M-2 and M-5) plasma concentrations, and may increase toxicity
              • Avoid concomitant use of regorafenib with strong CYP3A4 inhibitors (eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole)
            • Breast cancer resistance protein (BCRP) substrates
              • Coadministration with a BCRP substrate increases the BCRP substrate plasma concentrations
              • Closely monitor for signs and symptoms of exposure-related toxicity of the BCRP substrate (eg, methotrexate, fluvastatin, atorvastatin)
              • Consult the concomitant BCRP substrate product information when considering administration of regorafenib
            • UGT substrates
              • Regorafenib competitively inhibits UGT1A9 and UGT1A1 substrates
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            Pregnancy & Lactation

            Pregnancy

            Based on animal studies and mechanism of action, fetal harm may occur when administered to a pregnant woman

            There are no available data on use in pregnant women

            Advise pregnant women of the potential hazard to a fetus

            Animal data

            • Administration of regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations

            Contraception

            • Females: Use effective contraception during treatment and for 2 months following the final dose
            • Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 months following final dose

            Infertility

            • There are no data on the effect on human fertility
            • Results from animal studies indicate that regorafenib can impair male and female fertility

            Lactation

            There are no data on the presence of regorafenib or its metabolites in human milk, the effects of regorafenib on the breastfed infant, or on milk production In rats, regorafenib and its metabolites are excreted in milk

            Because of the potential for serious adverse reactions in breastfed infants from regorafenib, do not breastfeed during treatment and for 2 weeks after the final dose

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Tyrosine kinase inhibitor; shown to inhibit activity of membrane-bound and intracellular kinases involved in normal cellular functions and in pathological processes (eg, oncogenesis, tumor angiogenesis) RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl

            Absorption

            Bioavailability: 69-83% (with low fat meal)

            Peak Plasma Time: 4 hr

            Peak Plasma Concentration: 2.5 mcg/mL (single dose); 3.9 mcg/mL (steady-state)

            AUC: 70.4 mcg•h/mL (single dose); 58.3 mcg•h/mL (steady-state)

            Distribution

            Protein Bound: 99.5% (regorafenib); 99.8% (M-2 active metabolite); 99.95% (M-5 active metabolite)

            Undergoes enterohepatic circulation with multiple plasma concentration peaks observed during 24-hr interval

            Metabolism

            Metabolized by CYP3A4 and UGT1A9

            Metabolites (active): M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in vitro pharmacological activity and steady-state concentrations as regorafenib

            Elimination

            Half-life: 28 hr (regorafenib); 25 hr (M-2 active metabolite); 51 hr (M-5 active metabolite)

            Excretion: 71% feces; 19% urine (within 12 days of single dose)

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            Administration

            Oral Administration

            Administer orally same time each day

            Swallow table whole with water, do not split, chew, or crush

            Take after a low-fat meal that contains <600 calories and <30% fat

            Do not take 2 doses on the same day to make up for a missed dose from the previous day

            Storage

            Tablets: Store at 25°C (77°F); excursions are permitted from 15-30°C (59-86°F)

            Store tablets in the original bottle and do not remove the desiccant

            Keep the bottle tightly closed after first opening

            Discard any unused tablets 7 weeks after opening the bottle; dispose of unused tablets in accordance with local requirements

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            Images

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            Formulary

            FormularyPatient Discounts

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            • Compare formulary status to other drugs in the same class.
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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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